Isosorbide dinitrate (ISD) has been given orally like other nitric acid esters for angina pectoris in the form of tablets or capsules with good results for a long time. Recently it has been shown that apart from this traditional indication ISD can also be used for the following diseases: for heart insufficiency of the left ventricle, for recent myocardinfarct as well as for incipient edema of the lungs.
For the preceding indications the parenteral application offers advantages compared with the oral application since
The patients with the aforementioned diseases are in hospitals; PA1 A correct, controlled dosage by infusion is necessary; and PA1 When parenterally applied the metabolism of the active substance during the first passage through the liver is avoided, which leads, as is well known, to a decomposition of essential amounts of active substance to mononitrates and isosorbide when orally applied. PA1 Even the lowest possible starting concentration at the beginning of a treatment could be adjusted in the infusion solution; PA1 A sufficiently high concentration for the treatment could be attained without applying very large liquid amounts; and PA1 The calculation of concentrations would be considerably simplified by a simple ratio of numbers (e.g., 1 mg ISD/ml).
When ISD is parenterally applied, dosage should be made up individually according to the acuteness of the respective case. The ISD concentration in ampules for the production of infusion solutions aimed at by doctors should be 1 mg/ml (= g/l), 2 mg/ml (= 2 g/l) or more, since in this manner.
In general, the lowest concentration with which therapy can be started is regarded as 5 mg ISD/250 ml infusion solution. If ampules with ISD solutions having a concentration of 1 mg/ml were available, 5 ml of these ISD solutions would have to be diluted to 250 ml infusion solution. Then the dosage could be increased so that 10 mg ISD or even more a day could be applied to the patients.
On the basis of experiments preceding the invention (examples 1 to 2) the production of an aqueous ISD solution having a concentration of 1 mg/ml seemed to be impossible. At room temperature a saturation value of about 0.7 g ISD/1 was found. These experiments were carried out in the presence of solid ISD in a manner which is usual to find out saturation values; ISD was dissolved in water up to saturation at room temperature or it crystallized from an supersaturated solution which had been cooled to room temperature. The results correspond to published data. From the following table 1 there follows that the older published data (caused by inexactness) vary within a broad range and in the meantime this range has been limited to limits of about 0.5 and 0.7 g/l so that this range has been corrected.
Table 1 ______________________________________ solubility of ISD in water (g/l) Year Quotation ______________________________________ 2 1959 Med. Prom. SSSR 13 (1959) 18 - 20 according to CA 54 (1960) Quotation 8647 h 1.1 1968 Merck Index (1968) 593 0.001089 1968 Merck Index (1968) 593 &lt;0.5 1975 Anal. Profiles Drug Subst. 4 (1975) 231 0.68 1975 Needleman, Organic Nitrates, Springer (1975) 17 ______________________________________